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Downregulation
Down regulation is the process by which a cell decreases the number of receptors to a given hormone or neurotransmitter to reduce its sensitivity to this molecule. This is a locally acting negative feedback mechanism. An increase of receptors is called up regulation. Mechanism For insulin, the process of down regulation occurs when there are elevated levels of the hormone in the blood. When insulin binds to its receptors on the surface of a cell endocytosis of the hormone receptor complex is initiated, only to be subsequently attacked by intracellular lysosomal enzymes. The internalization is multi-purposed it provides the pathway for degradation of the hormone, and also a way to regulate the amount of sites that are available for binding on the cell’s surface. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by he accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to the elevated hormone concentration. The process of decreasing the number of receptor sites is virtually the same for all hormones it only varies in the receptor hormone complex. Cases To illustrate this process we shall look at the insulin receptor sites on the target cells of a Type II diabetic. Due to the elevated levels of blood glucose from excessive feeding in an overweight individual the β-cells (islets of Langerhans) in the pancreas must release more insulin than normally emitted to match the demand and return the blood to homeostatic levels. The near constant increase in blood insulin levels results from an effort to match the increase in blood glucose which will cause receptor sites on the person’s cell to down-regulate and decrease the number of receptors for insulin, increasing the subject’s resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance, which in turn leads to a case of adult onset diabetes in that subject. Other cases include Diabetes insipidus; here the kidneys become insensitive to arginine vasopressin. Reversal There are ways to counteract this process; using the previous example a Type II diabetic may increase their sensitivity to insulin through proper diet and regular exercise producing weight loss, some may even return to their pre-diabetic state following this regimen. Mathematical modelling * Receptor desensitization has been previously modeled in the context of a two-state mathematical model (see this link http://www.bio-balance.com/Graphics.htm) Reference Sherwood, L. (2004). “Human Physiology From Cells to Systems, 5th Ed” (p. 680). Belmont, CA: Brooks/Cole-Thomson Learning Wilmore, J., Costill, D. (2004). Physiology of Sport and Exercise, 3rd Ed (p. 164). Champaign, IL: Human Kinetics